Involvement of the ICE family of proteases in silica-induced apoptosis in human alveolar macrophages

Rashi Iyer, Andrij Holian

Research output: Contribution to journalArticlepeer-review

Abstract

Exposure to silica dust can result in lung inflammation that may progress to fibrosis for which there is no effective clinical treatment. The mechanisms involved in the development of pulmonary silicosis have not been well defined; however, most current evidence implicates a central role for alveolar macrophages in this process. We have previously demonstrated that fibrotic agents, such as asbestos and silica, induce apoptosis in human alveolar macrophages. The goal of this study was to identify molecular events in the silica-induced apoptotic process to better understand the mechanism by which fibrotic agents may be inducing apoptosis in human alveolar macrophages. To elucidate the possible mechanism by which silica causes apoptosis, we investigated the involvement of the interleukin-converting enzyme (ICE) family of proteases. Human alveolar macrophages were treated with silica in vitro and were examined for the involvement of ICE, Ich-1(L), and cpp32β in silica-induced apoptosis. Pretreatment of cells with 10 μM of the ICE inhibitor z-Val-Ala-Asp-fluoromethyl ketone and the cpp32β inhibitor Asp-Glu-Val-Asp-fluoromethyl ketone completely blocked silica-induced apoptosis. Additionally, an increased formation of the active p20 fragments of ICE and Ich-1(L) as well as degradation of the inactive zymogen form of cpp32β protein were observed in silica-treated human alveolar macrophages, indicating activation of these proteases. Furthermore, degradation of the nuclear protein poly(ADP-ribose) polymerase was observed within 2 h of silica treatment. These results suggest that silica-induced apoptosis involves activation of the ICE family of proteases and is the first step in elucidating the intracellular mechanism of particulate-induced apoptosis in human alveolar macrophages.

Original languageEnglish
Pages (from-to)L760-L767
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume273
Issue number4 17-4
DOIs
StatePublished - 1997

Keywords

  • cpp32β
  • Ich-1(L)
  • Interleukin-converting enzyme

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